Genomic, transcriptional and mutational analysis of the mouse microphthalmia locus

Mouse microphthalmia transcription factor (Mitf) mutations affect the devel opment of four cell types: melanocytes, mast cells, osteoclasts, and pigmen ted epithelial cells of the eye. The mutations are phenotypically diverse a nd can be arranged in an allelic series. In humans, MITF mutations cause Wa ardenburg syndrome type 2A (WS2A) and Tietz syndrome, autosomal dominant di sorders resulting in deafness and hypopigmentation. Mitf mice thus represen t an important model system for the study of human disease. Here we report the complete exon/intron structure of the mouse Mitf gene and show it to be similar to the human gene. We also found that the mouse gene is transcript ionally complex and is capable of generating at least 13 different Mitf iso forms. Some of these isoforms are missing important functional domains of t he protein, suggesting that they might play an inhibitory role in Mitf func tion and signal transduction. In addition, we determined the molecular basi s for six microphthalmia mutations. Two of the mutations are reported for t he first time here (Mitf(mi-enu198) and Mitf(mi-x39)), while the others (Mi tf(mi-ws), Mitf(mi-bws), Mitf(mi-ew), and Mitf(mi-di)) have been described but the molecular basis for the mutation nor determined. When analyzed in t erms of the genomic and transcriptional data presented here, it is apparent that these mutations result from RNA processing or transcriptional defects . Interestingly, three of the mutations (Mitf(mi-x39), Mitf(mi-bws), and Mi tf(mi-ws)) produce proteins that are missing important functional domains o f the protein identified in in vitro studies, further confirming a biologic al role for these domains in the whole animal.